| Summary: | Surgical procedures performed on blood vessels may cause irritation of the vessel
wall. This irritation sets off a series of complicated steps, which results in a growth of
the vessel wall towards the center of the blood vessel, and a narrowing of the amount of
space for the blood to flow through. This process is called restenosis.
Restenosis of the treated artery is a major complication of percutaneous
transluminal coronary angioplasty (PTCA) and coronary artery bypass grafting. This
intimal hyperplasia (thickening of the intimal layer of the blood vessel) is due to the
differentiation, migration, and proliferation of connective tissue and vascular smooth
muscle cells at the site of vascular injury (Mishaly, 1997). Through this process the
arterial lumen may be enclosed by the neointima and thus compromise coronary blood
flow.
Paclitaxel stabilizes microtubules and in this way inhibits differentiation of
vascular smooth muscle cells from a contractile phenotype to a migratory and
proliferative phenotype in vitro. In vivo paclitaxel has inhibited vascular smooth muscle
cell migration and proliferation in rabbits and in the rat carotid artery model. Drug
delivery to the adventitia of the blood vessel may target events occurring in the
adventitia, media, and intima. Perivascular drug delivery devices have delivered drugs
that reduce stenosis in arteries in animal models. The objective of this work was to
develop a flexible, biocompatible, paclitaxel loaded polymer film for perivascular
application, to provide controlled release of paclitaxel over several weeks.
Poly(ethylene-co-vinyl acetate) (EVA) with monomer ratios of 60/40 and
72/28, and polyurethane, were cast into films with various loadings of paclitaxel. These
polymers were chosen because of their biocompatibility, hydrophobicity, flexibility, and
because they are nondegradable. Perivascular films were manufactured from 60/40 EVA,
72/28 EVA or polyurethane, with various loadings of paclitaxel and sterilized by yirradiation.
The physicochemical properties, and diffusion and release characteristics of
paclitaxel in these films were investigated in this work.
Paclitaxel existed within the EVA matrices as a granular, amorphous solid,
whereas paclitaxel was miscible with the polyurethane matrices, y-irradiation of
paclitaxel loaded EVA films resulted in cross-linking of the polymer chains, whereas yirradiation
of polyurethane films resulted in polymer chain scission. Partitioning,
permeability, and diffusion coefficients of paclitaxel in EVA and polyurethane were
determined, and were similar for the two different types of matrices. Paclitaxel release
from EVA and polyurethane films was linear with the square root of time, and with the
square root of the loading concentration, for the first several days. Paclitaxel release
from EVA and polyurethane films was by diffusion without the creation of channels or
pores, and followed the Higuchi model of release for the first several days. Paclitaxel
release from 60/40 EVA, 72/28 EVA, and polyurethane, was influenced by polymer
monomer ratio, polymer type, and drug loading. Given the effects of sterilization on
paclitaxel loaded 60/40 EVA, 72/28 EVA, and polyurethane films, polyurethane films
showed the most promising potential for developing a film for the controlled release of
paclitaxel for perivascular application for the inhibition of restenosis. === Pharmaceutical Sciences, Faculty of === Graduate
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